The basic problem with prior art processes for the preparation of 2-chloro sulfinyl azetidinones from the reaction of a penicillin sulfoxide ester and an N-chloro halogenating agent resides in the unavoidable production at the elevated temperature of the reaction of large amounts of hydrochloric acid. The presence of the generated hydrochloric acid affects adversely the yield of the end product. In fact, if the hydrochloric acid is allowed to remain in the reaction medium, the azetidinone yield decreases considerably. It has, therefore, been the object of manufacturers to provide ways whereby the hydrochloric acid generated is neutralised.
Prior U.S. Pat. Nos. 4,052,387 and 4,081,440 disclose processes for the preparation of 2-chloro sulfinyl azetidine-4-one by the treatment of the corresponding penicillin sulfoxide ester with an N-chloro halogenating agent in an inert solvent, the reaction being carried out in the presence (or absence) of an alkene oxide acid scavenger such as propylene oxide or butylene oxide to remove any hydrochloric acid formed during the reaction. Unfortunately, the subsequent conversion of 2-chloro sulfinyl azetidin-4-one to 3-chloro-cephem carboxylate is exceedingly poor being only in the range of 25% to 40%.
U.S. Pat. No. 4,165,315 discloses a method similar to that of the two above-mentioned U.S. patents.
U.S. Pat. Nos. 4,075,203 and 4,165,316 disclose the employment of a combination of alkylene oxide and calcium oxide as a hydrochloric acid scavenger in the reaction of a penicillin sulfoxide ester with an N-chloro halogenating agent to produce 2-chloro sulfinyl azctidin-4-one.
U.S. Pat. No. 4,289,695 discloses the use of a weakly basic, organic solvent-insoluble poly-4-vinyl pyridine polymer partially cross-linked with divinylbenzene as the hydrogen chloride acceptor in the ring-opening reaction for the conversion of a penicillin sulfoxide ester to 2-chloro sulfinyl azetidin-4-one. The product thus produced on reaction with a Lewis acid gives the corresponding 3-exomethylene cepham sulfoxide ester in a yield of from 10% to 76%. Unfortunately, poly-4-vinyl pyridine polymer is costly and for economic consideration, the hydrochloride produced therefrom requires regeneration to the original base for re-use which makes the entire operation extremely lengthy.
Finally, U.S. Pat. No. 5,070,195 discloses a similar process for the preparation of 2-chloro sulfinyl azetidin-4-one employing anion exchange resins as the acid trapping agent. These resins are shown to have the following structures: ##STR3## wherein X is a chloride, hydroxide or sulfate ion.
However, unless the hydrochloric acid generated during the reaction is simply adsorbed by the anion exchange resins, it is difficult to rationalise how such acid can be trapped by means of quaternary ammonium functionality since that would be equivalent to the reaction of quaternary ammonium chloride or sulphate with hydrochloric acid. It is, therefore, not surprising that poor yields of 2-chloro sulfinyl azetidin-4-one are obtained when anion exchange polymeric quaternary ammonium compounds are used as acid trapping agents according to U.S. Pat. No. 5,070,195.